It is thought that the major cause of alcohol-induced liver injury is inflammation, and it is well known that women are more susceptible to alcoholic liver disease (ALD) than men. While increased circulating levels of the proinflammatory cytokine IL-6 are a marker for serious ALD in humans, little is known about the expression of its receptor (IL-6R?) and its activity during chronic alcohol administration. Preliminary studies in rats show clear gender differences at both the RNA and protein levels of alcohol-induced liver IL-6R? and I?B expression after up to four weeks of intragastric ethanol feeding. Liver STATS phosphorylation was found to be higher in females after two, but not four weeks of ethanol consumption, indicating a loss of signaling activity in spite of increased receptor expression. Conversely, ethanol-consuming males displayed increased I?B expression as compared to females, which may inhibit IL-6R? expression or function. Given the association of inflammation with ethanol induced liver damage, in this application we propose to: 1) Determine whether testosterone or estrogen directly affect the expression of IL- 6R? or I?B in the liver of ethanol consuming animals. To accomplish this, we intend to use the intragastric ethanol-feeding model of chronic ethanol consumption. Prior to ethanol exposure, ovarectomized rats will be implanted with subcutaneous, vehicle, testosterone or estrogen containing micro-osmotic pumps. Liver histopathology, mitogenesis, IL-6R?, and I?B mRNA and protein expression will be assessed after two and four weeks of ethanol exposure. 2) Determine if there is a relationship between IL-6R activation or over-stimulation and liver damage. While preliminary data indicates that IL-6R is upregulated in female ethanol consuming animals, there lacks a definitive link between the receptor and increased liver damage. Ovarectomized rats will be treated with recombinant IL-6R agonists via injection daily, during four-week ethanol feeding. Liver histopathology, circulating liver enzymes, and IL-6R signal transducing molecules will be assessed. By exposing ethanol- consuming rats to IL-6R agonists, it should be possible to correlate damage with receptor activation. [unreadable] [unreadable] [unreadable]